Comparative pharmacovigilance assessment of adverse events associated with the use of hydroxyurea, L‐glutamine, voxelotor, and crizanlizumab in sickle cell disease
Authors: Ming Chen, Jane S. Hankins, Min Zhang, Kenneth I. Ataga
Journal: American Journal of Hematology (2023)

Using disproportionality analysis, this study compared the adverse events (AEs) associated with the use of the new agents (e.g., L-glutamine, voxelotor, and crizanlizumab) to the commonly used medication, hydroxyurea, in sickle cell disease. We found that the most frequent drug-related AEs observed in this real-world study were consistent with those in the HOPE (voxelotor) and SUSTAIN (crizanlizumab) trials, but the rates of AEs were lower. Our study demonstrates that the most common AEs and symptoms of an increased risk associated with the individual drugs varied by treatment. Disproportionate reporting signals of drug-related AEs may also capture information that is independent of subjective measures of patient-reported symptoms. Our study highlights the important need for facilitating patient-physician communication in routine clinical care to understand patient-reported symptoms. Sickle cell disease (SCD) is an autosomal recessive blood disorder caused by a mutation in the β-globin gene, producing abnormal sickle hemoglobin (HbS). Currently, four pharmacological disease-modifying therapies with different mechanisms of action are approved for the treatment of SCD in the United States (US): hydroxyurea (S-phase inhibitor agent), L-glutamine (conditionally essential amino acid), voxelotor (HbS polymerization inhibitor), and crizanlizumab (P-selectin inhibitor). Existing evidence from randomized, double-blind clinical trials has demonstrated significant efficacy of hydroxyurea,1 L-glutamine,2 and crizanlizumab3 in reducing the frequency of acute pain episodes in patients with SCD. While the recently completed phase 3 trial of crizanlizumab versus placebo did not confirm its efficacy in decreasing the frequency of pain crises, no new safety concerns were reported.4 With the approvals of L-glutamine in 2017, and voxelotor and crizanlizumab in November 2019 by the US Food and Drug Administration (FDA), health care providers now have more options for the treatment of patients with SCD. Despite favorable benefits, drug-related adverse events (AEs) have been reported.3, 5 Patient-reported symptoms such as headache, fatigue, nausea, diarrhea, and extremity pain were observed in both the HOPE trial for voxelotor5 and the SUSTAIN study for crizanlizumab3 as drug-related AEs. Although patient-reported symptoms are considered important factors to measure the safety and tolerability of drugs in clinical trials, they are rarely captured in population-based claims databases in the real-world setting. Real-world evidence regarding the comparative assessment of AEs of these pharmacological treatments for SCD is largely unknown, especially comparing the new agents (e.g., L-glutamine, voxelotor, and crizanlizumab) with the commonly used medication, hydroxyurea. To examine the AEs associated with the use of approved drug therapies for SCD, we retrospectively analyzed the FDA Adverse Events Reporting System (FAERS) database, which includes quarterly data files of AE reports spontaneously submitted to the FDA since 2004. Data on AE reports of the four drugs as the primary or secondary treatments for SCD from the 1st quarter of 2020 to the 4th quarter of 2022 were extracted. Drug-related AE reports were identified using text strings of each treatment's proprietary name, nonproprietary names, abbreviations, and potential misspellings. A treatment indication for SCD or sickle cell anemia but not for sickle cell trait, thalassemia minor, or beta thalassemia without HbS was required to ensure that the AE reports were for individuals with SCD. Detailed sample selection criteria are defined in Figure S1. Study outcomes including pain and non-pain symptoms associated with the drug therapies were identified using the preferred terms of the Medical Dictionary for Regulatory Activities. Pain symptoms were further classified by site, and non-pain symptoms included fatigue, diarrhea, nausea, and other AEs as reported in the HOPE trial.5 Separate disproportionality analyses using two-by-two contingency tables for each symptom examined the disproportionate reporting signals of AEs associated with the use of L-glutamine, voxelotor, and crizanlizumab, compared with hydroxyurea. Hydroxyurea was chosen as the reference drug because it is widely used as a first-line treatment for SCD, with significant efficacy in increasing fetal hemoglobin and decreasing acute pain episodes. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) were calculated. The ROR is calculated as the odds of targeted AEs for the comparison drug divided by the odds of corresponding AEs for hydroxyurea. A disproportionality threshold of ROR >2 with the lower bound of 95% CI >1 indicates a potential signal of increased risk.6 Stratified by AE severity, sensitivity analyses of RORs were conducted, with Breslow-day tests for the homogeneity of RORs. Severity of AE was a binary indicator of the occurrence of any adverse reactions reported for the treatment, including death/life-threatening, hospitalization, and other serious events. Among serious AEs (e.g., death and hospitalization) reported for each treatment, disproportionality analyses of the treatment-event association were further conducted. All statistical analyses were performed in RStudio (Version 4.2.3) and SAS 9.4. Characteristics of a total of 21 171 AE reports which included 58 473 individual AEs for the four drugs are shown in Table S1. Of these, AEs were most frequently reported for voxelotor (N = 18 961 reports and 49 084 AEs). Significant differences in patient sex, age, and other characteristics of AE reports by treatment were found (all p < 0.05). Figure S2 shows the annual prevalence of targeted AEs per 1000 reports. On average, the most prevalent non-pain symptoms were fatigue (88/1000 report-year), nausea (63/1000 report-year), and diarrhea (51/1000 report-year). Among pain symptoms, headache (50/1000 report-year), bone pain (27/1000 report-year), and arthralgia (22/1000 report-year) were most prevalent. Specifically, patients on L-glutamine or crizanlizumab frequently reported diarrhea, nausea, headache, and upper abdominal pain; patients on voxelotor frequently reported pain symptoms (e.g., back pain, arthralgia, and extremity pain); patients on hydroxyurea more frequently reported headache, extremity pain, bone pain, and upper abdominal pain. Results on the proportions of targeted AEs among total reports demonstrate similar patterns (Figure S3). Compared with hydroxyurea, the RORs (95% CIs) for fatigue associated with the use of L-glutamine, voxelotor, and crizanlizumab were 0.33 (0.15–0.70), 1.08 (0.89–1.30), and 0.99 (0.73–1.34), respectively (Table 1). In comparing voxelotor and crizanlizumab to hydroxyurea, diarrhea, and nausea were more likely with voxelotor (both ROR >2), while diarrhea, vomiting, and rash appeared less likely with crizanlizumab (all ROR <2), and pyrexia was more likely with crizanlizumab (ROR >2). Table 2 presents the RORs of drug-related AEs on pain by site and treatment. Overall, disproportionate reporting signals of AEs for pain by site were smallest for hydroxyurea with the lowest RORs. Symptoms of headache and abdominal pain were most likely reported for voxelotor; upper abdominal pain and extremity pain were most likely with L-glutamine; chest pain, back pain, and arthralgia were most likely with crizanlizumab. Sensitivity analyses of RORs demonstrated that most disproportionate reporting signals of AEs did not significantly differ by AE severity for each treatment (Tables S2 and S3). Among serious AEs reported for each treatment, hospitalization was the most prevalent. Significant disproportionate reporting signals were observed for all types of drug-related serious AEs for SCD (Table S4). While the demonstrated efficacy of voxelotor and crizanlizumab suggests favorable therapeutic profiles, real-world evidence on the comparative pharmacovigilance assessment of AEs of these drugs to hydroxyurea or L-glutamine is lacking. In this disproportionality analysis of FAERS data, we found that non-pain symptoms were mostly associated with the use of hydroxyurea, whereas pain symptoms were more strongly associated with the use of voxelotor and crizanlizumab. This comparative pharmacovigilance study is the first to date to provide measurable disproportionate reporting signals of clinically important symptoms of drug-related AEs among approved pharmacological therapies for SCD. Stratified by AE severity, we only found significant differences in the RORs of nausea and headache comparing each targeted treatment to hydroxyurea. Nausea and headache were less likely to be reported in patients with versus those without adverse reactions. On the other hand, symptoms with homogeneous disproportionate reporting signals may be sustained, including most pain symptoms. Existing evidence demonstrates that headache and abdominal pain are side effects of treatment with voxelotor.5 Although acute pain episodes are a clinical hallmark of SCD, and measures of the severity of pain are subjective, it is important to consider whether pain symptoms are related to the disease or the treatment. The most frequent drug-related AEs observed in this real-world study were consistent with those in the SUSTAIN (crizanlizumab) and HOPE (voxelotor) trials, but the rates of AEs were lower,3, 5 possibly indicating underreported AEs in the FAERS database. Confounding by indication, non-reporting of AEs, insufficient treatment duration, and nonadherence to the treatment may contribute to underreporting. In the SUSTAIN trial, drug-related AEs were captured over a 52-week treatment phase, while the median treatment duration in the HOPE trial was approximately 72 weeks for the two doses of voxelotor. It is possible that the treatment duration was not long enough to capture sufficient AEs for patients in the FAERS database compared with patients in the trials, resulting in lower AE rates. While varying rates of AEs by dose were suggested from the trials, such information was unreliable in the database. This study had some limitations. First, drug-related AEs in the FAERS database are prone to reporting bias. However, this is one of the few ways to capture these symptoms, which are based on patient self-report. Second, the signal detection methods only identify the relative RORs of symptoms and are limited in providing estimations with adjustment for confounders (e.g., comorbidities, treatment history, duration, and adherence). These confounders are unavailable or incomplete in the database. Third, the database has limited information on laboratory AEs related to the treatments (e.g., cytopenias may result from treatment with hydroxyurea). Fourth, there may be misclassification of serious AEs, as severity was defined based on the reports submitted to the FDA. RORs for certain symptoms may also be conservative with inadequate internal validity due to a limited number of AEs. Finally, drug-related AEs for voxelotor may be over-represented in the database as voxelotor was conditionally approved by the FDA based on a surrogate endpoint, and AEs were obligately reported to the FDA. In summary, this study provides important evidence on the comparative pharmacovigilance assessment of drug-related AEs among the four currently FDA-approved disease-modifying agents for SCD. Disproportional signals on the most common AEs and symptoms of an increased risk associated with the individual drugs varied by treatment, which highlights the need for facilitating patient-physician communication in routine clinical care to understand patient-reported symptoms. The moderate-to-strong disproportionate reporting signals of drug-related AEs may also capture information that is independent of subjective measures of patient-reported symptoms, and health care providers should be aware when making treatment choices. Future comparative studies or pragmatic trials to assess AEs related to disease-modifying agents for SCD are needed. Ming Chen contributed to conceptualization, study design, methodology, formal analysis, interpretation of results, writing – original draft, and writing – review and editing. Jane S. Hankins contributed to interpretation of results and writing – review and editing. Min Zhang contributed to methodology and writing – review and editing. Kenneth I. Ataga contributed to conceptualization, interpretation of results, supervision, and writing – review and editing. The authors received no financial support for the research, authorship, and/or publication of this article. Ming Chen: AbbVie: Ended employment in the past 24 months. Kenneth I. Ataga: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Agios Pharmaceuticals: Honoraria and Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy and Honoraria; Biomarin: Consultancy and Honoraria; Pfizer: Honoraria and Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Honoraria and Membership on an entity's Board of Directors or advisory committees; Vertex: Other: Data Monitoring Committee; Takeda Pharmaceuticals: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Hillhurst Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; NHLBI: Research Funding; FDA: Research Funding. Other authors declare no conflicts of interest in relation with this manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Characteristics of adverse event (AE) reports on treatments for SCD (2020–2022). Table S2. Sensitivity analyses of RORs of non-pain symptoms by AE severity. Table S3. Sensitivity analyses of RORs of pain symptoms by AE severity. Table S4. RORs of different types of serious AEs associated with the treatment. Figure S1. Sample selection diagram (2020–2022). Figure S2. Annual prevalence of targeted drug-related AEs per 1000 reports (2020–2022). (A) Non-pain symptoms; (B) Pain symptoms, by site. Figure S3. Proportion of targeted drug-related AEs among total reported events (2020–2022). (A) Non-pain symptoms; (B) Pain symptoms, by site. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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